Alshahrani et al.

Trials (2019) 20:286

https://doi.org/10.1186/s13063-019-3394-4

STUDY PROTOCOL Open Access

Study protocol for a randomized, blinded,

controlled trial of ketamine for acute
painful crisis of sickle cell disease
Mohammed S. Alshahrani1* , Laila Perlas Asonto1, Mohamed M. El Tahan2, Amal H. Al Sulaibikh3,
Sukayna Z. Al Faraj3, Abdullah A. Al Mulhim3, Murad F. Al Abbad3, Samar A. Al Nahhash3, Moath N. Aldarweesh3,
Alaa M. Mahmoud3, Nisreen Almaghraby3, Mohammed A. Al Jumaan3, Thamir O. Al Junaid3, Faisal M. Al Hawaj3,
Samar AlKenany3, Omaima F. ElSayed3, Haitham M. Abdelwahab3, Mohamed M. Moussa3, Bader K. Alossaimi3,
Shaikah K. Alotaibi3, Talal M. AlMutairi3, Duaa A. AlSulaiman4, Saad D. Al Shahrani3, Donia Alfaraj3 and
Waleed Alhazzani5

Abstract
Background: Sickle cell disease (SCD) is an inherited hematological disorder where the shape of red blood cells is
altered, resulting in the destruction of red blood cells, anemia, and other complications. SCD is prevalent in the
southern and eastern provinces of the Arabian peninsula. The most common complications for individuals with
SCD are acute painful episodes that require several doses of intravenous opioids, making pain control for these
individuals challenging. Instead of opioids, some studies have suggested that ketamine might be used for pain
control in acute pain episodes of individuals with SCD. This study aims to evaluate whether the addition of
ketamine to morphine can achieve better pain control, decreasing the number of repeated doses of opiates. We
hypothesize that early administration of ketamine would lead to a more rapid improvement in pain score and
lower opioid requirements.
Methods and analysis: This study will be a prospective, randomized, concealed, blinded, pragmatic parallel group,
controlled trial enrolling adult patients with SCD and acute vaso-occlusive crisis pain. All patients will receive
standard analgesic therapy during evaluation. Patients randomized to the treatment arm will receive low-dose
ketamine (0.3 mg/kg in 0.9% sodium chloride, 100 ml bag) in addition to standard intravenous hydration, while
those in the control group will receive a standard dose of morphine (0.1 mg/kg in 0.9% sodium chloride, 100 ml
bag) in addition to the standard intravenous hydration. All healthcare providers will be blinded to the treatment
arm. Data will be analyzed according to the intention-to-treat principle. The primary outcome is improvement in
pain severity using the Numerical Pain Rating Score.
Trial registration: Clinicaltrials.gov, NCT03431285. Registered on 13 February 2018
Keywords: Acute painful crisis, Ketamine, Randomized control trial, Sickle cell disease

* Correspondence: msshahrani@iau.edu.sa
1
Emergency and Critical Care Departments, King Fahad Hospital of the
University, Imam Abdulrahman bin Faisal University-Dammam, AlKhobar,
Kingdom of Saudi Arabia
Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Alshahrani et al. Trials (2019) 20:286
Background and rationale
Sickle cell disease (SCD) is an inherited hematological dis-
order where the shape of red blood cells is altered into
sickle-like cells resulting in the destruction of red blood
cells leading to anemia and other hematological complica-
tions. SCD is prevalent in the southern and eastern prov-
inces of the Arabian peninsula. Acute painful episodes are
the most common complications of the disease process;
they result from tissue ischemia due to occlusion of the
microcirculation with clusters of sickled red blood cells
[1]. These episodes usually involve the long bones or the
spine and might also involve other organs. An acute pain-
ful crisis can be precipitated by cold exposure, dehydra-
tion, infection, hypoxia, acidosis, or hypercarbia, or it may
not be related to a specific trigger. This condition exposes
the patient to severe pain requiring several emergency de-
partment (ED) visits, and is considered the most common
cause of hospital admissions for SCD patients. The costs
of hospital admission for SCD patients have been investi-
gated and, in the United States between 1989 and 1993,
75,000 admissions per year of SCD patients generated a
total cost of $475 million per year [2]. Patients with more
than three admissions per year with painful crises were
found to be at higher risk of early death [3]. The mainstay
of therapy for acute painful crisis is hydration and intra-
venous (IV) opioid analgesia [4]. Existing evidence sup-
ports the use of opioid therapy in treating vaso-occlusive
crises (VOCs) [5–9]. Nevertheless, the regimen of pain
control is challenging for the emergency physician be-
cause the management of acute painful crisis requires sev-
eral doses of IV opioids accompanied by the fear of
known side effects and complications associated with
these drugs. A study of SCD patients treated for painful
crisis showed that an accumulative dose of IV morphine
ranged from 4 mg to 26.7 mg with an average dose of
0.05–0.5 mg/kg during 70% of the visits. Fifty percent of
SCD patients were admitted at less than 3 h after ED treat-
ment, while 28% of the discharged patients returned to
the ED within 3 days [10]. Moreover, as with other chronic
pain patients, SCD patients experience opioid-induced
hyperalgesia leading to activation of the N-methyl-D-as-
partate (NMDA) receptors [1].
Ketamine, a noncompetitive NMDA receptor antagon-
ist, may have the potential to modulate opioid-induced
hyperalgesia through impaired sensitization of spinal
neurons to nociceptive stimuli, and may therefore re-
duce neuropathic pain. An extensive search of the litera-
ture revealed few reports on low-dose ketamine in the
management of acute painful crises in SCD patients.
The results of these reports were limited by their retro-
spective designs and the inclusion of relatively small
sample sizes [11–13].
A retrospective study of five children and adolescents
receiving low-dose ketamine infusion demonstrated a
Page 2 of 7
reduction in pain scores in two patients and a significant
reduction in opioid utilization in only one patient [12].
A recent Canadian retrospective study adding intraven-
ous ketamine in the management of nine patients with
painful sickle cell crisis showed significant reductions in
cumulative morphine consumption (146 ± 16.5 mg/day
versus 112 ± 12.2 mg/day) and pain scores [14]. Similar
reductions in opioid consumption were observed in a
retrospective American study of 30 SCD patients with
VOC pain [4]. In 2017, Motov et al. [15] performed a
prospective, randomized, double-dummy trial where
they investigated the analgesic efficacy and adverse ef-
fects of low-dose ketamine either by single IV push or
short infusion. The authors found that short infusion
was associated with significantly lower rates of unreality
feeling and sedation while achieving the same analgesic
efficacy of a single IV push.
To the best of our knowledge, there are no previously
published large, prospective, randomized controlled tri-
als investigating the impact of adding low-dose ketamine
on improving the quality of analgesia in patients with
VOC in SCD patients.
Aims and hypotheses
Primary hypothesis
We hypothesize that early administration of ketamine in
combination with standard acute opiate treatment will
achieve a more rapid reduction in pain score defined as
an improvement in the Numerical Pain Rating Score
(NPRS) of 1.5 points or more compared with the control
arm for pain relief in SCD patients with VOC pain.
Primary efficacy aims
The primary efficacy aim of our study is to validate
whether the early use of ketamine for the management
of acute sickle cell pain crisis will achieve a more effect-
ive reduction in pain severity scores.
Safety aim
Administration of either morphine or ketamine will ad-
here to standard practice and should not be considered
to pose any special safety issues. Nevertheless, monitor-
ing of patients will be performed for the possibility of
ketamine-related side effects, both common (nausea,
vomiting, and a mild increase in heart rate and blood
pressure) and uncommon (laryngospasm, emergence re-
actions, and nightmares). There is no reason to expect
that the incidence will exceed what is encountered in
daily practice [16].
Our clinical research data manager is tasked with
compiling and reviewing on a regular basis the accumu-
lating data collected to ensure the continuing safety of
current participants and those yet to be enrolled. Once
any protocol deviation/violation is identified, the issue
Alshahrani et al. Trials (2019) 20:286
shall be forwarded by the data manager to the safety
monitoring team to handle the deviation/violation.
Secondary efficacy aims
Secondary aims will be to decrease the ED length of stay,
the cumulative use of opioid during ED stays, the rate of
hospital admission (defined as the number of patients
who needed hospital admission from the ED due to refrac-
tory painful crises as opposed to those who were dis-
charged home from the ED) in both arms, and the
development of any known side effects of the drugs used.
Trial design
This study is a prospective, randomized, concealed,
blinded, pragmatic parallel group, controlled trial evalu-
ating the efficacy and safety of ketamine in combination
with standard treatment for the management of acute
pain crisis among SCD patients.
Methods
This study protocol is reported in accordance with the
SPIRIT statement guidelines to promote study quality
and transparent interpretation and reporting of study re-
sults [17] (Additional file 1).
Patient and public involvement
No patients were involved either in the trial design or
recruitment or any part of the study methods. Ketamine
has been widely used as a pain medication in our hos-
pital with an observed positive response. Saudi Food and
Drug Authority (SFDA) approval was obtained prior to
the use of this medication in the trial as an off-label in-
dication. All patients recruited signed an informed con-
sent, and a thorough trial procedure description between
patient and assessor contact was undertaken.
Study setting
The trial will take place at the ED of a tertiary academic
hospital in the eastern province of Saudi Arabia. All pa-
tients, irrespective of allocation, will receive a standard
dose of non-narcotic analgesia, within 30 min of
physician-patient contact with a single dose of either
paracetamol (1 g IV infusion over 30 min) or nonsteroi-
dal anti-inflammatory drugs (NSAIDS; either lornoxicam
8–16 mg IV or diclofenac 75 mg intramuscular injection)
since it is not ethical to deprive the patient of any kind
of analgesia while waiting for screening, randomization,
and study drug preparation. The pain score will be
measured at 0 and 30 min, after which the consent pro-
cedure and randomization will be initiated for patients
meeting these criteria: 1) established diagnosis of the
painful crisis; and 2) patients with an NPRS greater
than 5.
Page 3 of 7
The infusion preparation will be labeled for the patient
with a study number from the computer-generated
stratification numbers without any other identifying
marks. The study nurse assigned to the patient will ad-
minister the study drug. Patients, healthcare providers,
and outcome assessors will be blinded to the treatment
allocation.
Pain scores will be checked at 0, 30, 60, 90, 120 ,and
180 min after the study drug is given.
If no pain relief is achieved within 30 min of the study
drug being given, the treating physician will decide to ei-
ther resume usual practice with morphine or any equiva-
lent pain medication or make an admission decision
within a maximum of 180 min. Monitoring of all pa-
tients includes electrocardiography, noninvasive blood
pressure, pulse oximetry, and temperature. All patients
will receive oxygen supplementation through a face
mask or nasal prongs during sleep and when required to
maintain oxygen saturation higher than 92%. Lactated
Ringer’s or NaCl 0.9 solution will be infused at a rate of
2–3 ml/kg/h. Normothermia will be maintained with
warming air-enforced blankets if necessary. No attempt
will be made to expedite this process. All patients will be
included in the intension-to-treat analysis whether ad-
mitted or not.
Eligibility criteria
We will include patients who signed an informed con-
sent who meet the following criteria: 1) patients who are
18 years of age or older diagnosed with SCD based on
sickle cell tests or hemoglobin electrophoresis; 2) SCD
patients with acute onset of painful crisis developing
within 7 days from study recruitment.
Exclusion criteria
Patients with the following characteristics will be ex-
cluded from the study: 1) pregnancy or breast-feeding;
2) patients with altered mental status; 3) patients with
body mass index greater than 40 kg/m2; 4) patients with
significant neurological disease; 5) patients with seizures;
6) patients with acute head or eye injury; 7) patients with
high intracranial pressure; 8) patients with known psy-
chiatric disorders; 9) patients with significant cardiac
diseases or arrhythmias; 10) patients with significant pul-
monary diseases other than acute chest syndrome; 11)
patients with significant renal disease (BUN/creatinine
ratio < 25); 12) patients with significant hepatic disease
(Child-Pugh class B or C); 13) patients with significant
endocrine disease; 14) patients with a known allergy to
phencyclidine derivatives, ketamine, or morphine; 15)
patients with sepsis or septic shock; 16) patients who re-
quire circulatory or ventilatory support; 17) patients
with alcohol or drug abuse; 18) patients with chronic
pain status unrelated to SCD; 19) patients receiving
Alshahrani et al. Trials (2019) 20:286
anticonvulsant or antipsychiatric medications, narcotics,
or analgesics other than paracetamol and NSAIDs; or
20) patients with communication barriers.
Recruitment and consent
All physicians and nurses at the ED will be invited to an
in-service trial lecture. Pharmacy staff shall be invited to
attend this lecture to be conducted by the principal in-
vestigator to encourage screening of patients during
their shift for adult patients with SCD who will be ad-
mitted to the ED for severe painful crisis management
with pain NPRS greater than 5 on a standard range from
0 (no pain) to 10 (worst pain imaginable) who require
opioid analgesia determined by the attending physician.
Upon identification of patients, the study investigators
shall screen potentially eligible patients with the inclu-
sion/exclusion criteria checklist as per the data collec-
tion instrument. If the patient is eligible, study
investigators will obtain informed consent and explain
potential risks and benefits of receiving study interven-
tions (Additional files 2 and 3).
Interventions
Patients randomized to the intervention group will re-
ceive low-dose ketamine (0.3 mg/kg) in 100 ml normal
saline infused over 30 min in addition to a standard IV
hydration. Rescue pain medication will then be given to
patients based on the discretion of the treating phys-
ician. Patients randomized to the control group will re-
ceive the standard dose of morphine (0.1 mg/kg) in 100
ml normal saline infused over 30 min in addition to a
standard IV hydration. Rescue pain medication will then
be given to patients based on the discretion of the treat-
ing physician. The infusion preparation will be labeled
for the patient with the study number from the
computer-generated stratification numbers without any
other identifying marks. The study nurse assigned to the
patient will administer the study drug.
Study medications
We will investigate the addition of low-dose ketamine
(0.3 mg/kg) in 100 ml normal saline infused over 30 min
in addition to standard IV hydration in SCD patients
with acute VOC.
Concomitant medications
Upon arrival and assessment, and within 30 min of
patient-physician contact, all patients will receive a
standard dose of non-narcotic analgesia of either para-
cetamol 1 g IV infusion over 30 min or NSAIDS (either
lornoxicam 8–16 mg IV or diclofenac 75 mg intramuscu-
lar injection).
Page 4 of 7
Sample size
The sample size was based on the primary efficacy ana-
lysis of the mean score for pain, which was tested at a
two-sided significance level of 0.05. Based on the as-
sumptions of a standard deviation of 3.41, a mean differ-
ence among the groups of 1.5 in the score, and a power
of 90%, 220 patients are required. We need to recruit
240 patients since we used the Lan-DeMets O’Brien
Fleming approach for interim analysis using a two-sided,
asymmetric, beta-spending with nonbinding lower
bound at the 0.044 significance level. Additional patients
(10%) will be added for a final sample size of 264 pa-
tients to compensate for drop-outs during the study.
Blinding, allocation, and concealment
We intend to blind participants, healthcare providers, and
outcomes assessors to treatment allocation. After a patient
is considered eligible and written informed consent is ob-
tained, randomization will be performed. An unblinded
nurse with no involvement in patient care will randomize
the patients via an online, computer-generated sealed en-
velope program wherein randomization and treatment al-
location is concealed. Block size will be used to randomize
patients and stratify them according to gender to ensure
that the groups are balanced. We will randomize patients
in a 1:1 ratio to receive either low-dose ketamine (0.3 mg/
kg) in 100 ml normal saline in addition to standard IV hy-
dration or a standard dose of morphine (0.1 mg/kg) in
100 ml normal saline in addition to a standard IV hydra-
tion. All enrolled patients will receive the same design of
follow-up. We will use the intention-to-treat principles for
all analyses.
Unblinding
In the case of an adverse event (respiratory depression,
severe hypotension, laryngeal spasm, severe allergic reac-
tion, or cardiac arrest), an independent safety monitor-
ing team mandated to identify, evaluate, minimize, and
appropriately manage risks will take over. The team con-
sists of qualified independent investigators and clinicians
who will unmask treatment allocation and will provide
immediate medical care to subjects enrolled in the trial.
Co-interventions
The ED team will have full independent control of pa-
tient management, and any other management shall not
be influenced by the allocated intervention. As an ex-
ample, the ED physician will decide when and what to
give as rescue pain medication as usual practice.
Moreover, there will be predefined discharge criteria
where patients will be discharged after a minimum of
120 min (2 h) of receiving the study drug if the following
criteria are fulfilled: 1) fully awake Glasgow Coma Scale
Alshahrani et al. Trials (2019) 20:286
(GCS) score = 15/15; 2) stable vital signs; 3) able to walk
independently; and 4) no side effects related to the study
drugs.
Conversely, the admission decision will be taken
within a maximum of 180 min (3 h) if the following situ-
ations occur: 1) patients NPRS remains more than 5; 2)
unstable vital signs for any reason; 3) any side effects re-
lated to the study drugs; or 4) at the discretion of the
ED physician.
Measures and outcome measures
The primary efficacy outcome will be pain severity
scores using the NPRS; the patient will be asked to rate
their pain at the initial assessment and then the score
will be recorded by the ED nurse every 30 min until a
maximum of 180 min, whereupon either a discharge or
an admission decision will be made (which may have
already been taken based on the abovementioned prede-
fined criteria or discretion of the ED physician). Second-
ary outcomes include the length of ED stay (defined as
the time from the start of the study medication to the
discharge from the hospital or admission), the cumula-
tive use of opioids, the hospital admission rate, and the
incidence of any drug-related side effects.
Statistical methods
All data analyses will be carried out according to a
pre-established analysis plan. We are planning for
complete case analysis and multiple imputations for
missing data. All data will be analyzed according to the
intention-to-treat principle beginning immediately after
randomization.
Demographic and baseline disease characteristics will
be summarized with the use of descriptive statistics. Cat-
egorical variables will be reported as absolute numbers
and percentages. A generalized linear model will be used
to compare the two treatment groups. Categorical data
and 95% confidence intervals will be calculated by
means of the two-by-two table method with the use of
log-normal approximation. Continuous variables will be
reported as mean ± standard deviation (SD) or median
and interquartile range (IQR). Normality will be evalu-
ated using visual histogram evaluation and a Q-Q plot.
Between-group differences will be evaluated using the t
test or Wilcoxon signed rank test, in accordance with
normality of the distribution.
Sample size calculation was performed using both PS
(Power and Sample Size Calculator, Vr3.04, 2009 http://
biostat.mc.vanderbilt.edu/PowerSampleSize) and in the
R (R Foundation for Statistical Computing, Vienna,
Austria; https://www.R-project.org).
Data analysis will be performed using SPSS (v 16.0 for
Windows, IBM) and IBM SPSS Statistics v 25 will be
used to calculate the boundaries.
Page 5 of 7
Interim analysis
An independent safety committee will perform three in-
terim analyses on information time 25% (70 patients),
50% (140 patients), and 75% (210 patients). Data evalu-
ation at each interim analysis will be based on the alpha
spending function concept using a Lan-DeMets O’Brien
Fleming approach with the use of a two-sided, asymmet-
ric, beta spending with nonbinding lower bound. For the
first interim analysis the efficacy-stopping rule would re-
quire an extremely low P value (P < 0.000015). For the
second interim analysis, P < 0.0015 will be taken as the
efficacy stopping rule. For the third interim analysis, P <
0.0081 will be taken as the efficacy stopping rule. Inves-
tigators will be kept blinded to the interim analysis
results.
Monitoring
A research coordinator, study investigator, or the study
nurse will approach the patient to assess and record pri-
mary and secondary outcomes at the designated time in-
tervals. Data are collected by the bedside research nurse
upon enrollment on paper case report forms (CRFs). All
enrolled patients will receive a random patient identifi-
cation code. The paper data will be forwarded by the re-
search nurse to the data manager at the end of the
180-h window and will be transcribed electronically and
stored digitally, encrypted with a double password, with
the hard copy under lock and key. Access to the
data-entry system is managed and protected by a per-
sonalized username and is password protected.
Missing data will be accounted by complete case ana-
lysis and multiple imputations by the data manager, data
safety monitoring team, and a statistician.
We will describe serious adverse events as any mani-
festation, incident, or response to intervention, whether
anticipated or not that requires an in-patient admission
or extension of an existing hospitalization that results in
disability, life-threatening occurrence, or death.
The issue of the safety of the ED patients is a prime
concern in this pragmatic randomized clinical trial. Any
unexpected safety concerns will be reported to an inde-
pendent Institution Safety Monitoring Board who will be
monitoring the safety of the trial.
Approval of the study protocol
Prior to the start of the study, the protocol and the in-
formed consent form and other applicable documenta-
tion were approved by the Institutional Review Board
(IRB-2016-01-042) of our institution. Documentation of
Ethics Committee/IRB approvals are required before
projects are activated to register and enroll patients.
All signed informed consents will be stored in the
emergency department research office. The paper data
collection sheets and signed informed consents will be
Alshahrani et al. Trials (2019) 20:286
stored in a locked cabinet for safe keeping and made
available for trial-related monitoring, audits, and institu-
tional review board and regulatory inspections when re-
quired. Federal regulations require research records to
be retained for at least 3 years after the completion of
the research (45 CFR 46) and will be destroyed at a max-
imum of 5 years after publication. Only the data man-
ager will have access to the electronic database.
Discussion
Opioid treatment is currently the mainstay of VOC pain
management for SCD patients. However, the long-term
use of opioids is limited by the development of opioid
tolerance and opioid side effects such as respiratory de-
pression, hypotension, and histamine release. In
addition, opioid-induced hyperalgesia highlights the ne-
cessity for alternative pain management strategies for
these patients. Recently, a better understanding of the
pathophysiological mechanisms of VOC pain has led to
the development of new classes of drugs that are being
tested to provide better pain management for SCD pa-
tients with VOC and to overcome the limitations of opi-
oid use.
Activation of NMDA receptors has been found in SCD
patients and is suggested to be implicated in opioid-in-
duced hyperalgesia [1]. This finding led to the hypothesis
that NMDA antagonists might provide additional benefit
for VOC pain control.
Ketamine, a noncompetitive NMDA receptor antagon-
ist, may have the potential to modulate opioid-induced
hyperalgesia through impaired sensitization of spinal
neurons to nociceptive stimuli, and may therefore re-
duce neuropathic pain. Lubega et al. [18] performed a
randomized controlled trial in pediatric patients with
SCD and found that 1 mg/kg of IV ketamine was not in-
ferior to 0.1 mg/kg morphine in terms of maximum im-
provement in NPRS scores among SCD children with
acute severe VOC pain.
Several reports have described successful VOC pain
reductions with ketamine infusion [19]. Palm et al. [20]
reported a retrospective case series of five SCD patients
with prolonged VOC and insufficient pain control with
opioid analgesic therapy. The patients were treated with
continuous low-dose ketamine infusion up to 5 μg/kg/
min. The pain scores were significantly reduced by keta-
mine infusion, while only one of the five patients re-
ported vivid dreams as an adverse effect of ketamine.
These reports show that ketamine provides better pain
control as an adjuvant to opioids. However, the small
number of patients and the lack of a reliable control
group limit such reports.
The predictors of patient response to ketamine and
opioids were investigated by Nobrega et al. [21]. They
studied a cohort of 84 patients receiving 181 ketamine
Page 6 of 7
infusions. The multivariate analysis showed that gender,
age group, pain location, and infusion duration inde-
pendently predicted changes in pain score. They con-
cluded that male patients (P = 0.013) of younger age (P
= 0.018) achieved greater pain reductions than females
and older patients.
Published data regarding ketamine for VOC pain man-
agement are based on reports with small sample sizes or
retrospective designs that limit the generalizability of
their findings. In addition, some studies reported the use
of ketamine as an adjuvant to opioids. We realized the
necessity to provide a direct comparison between
low-dose ketamine and opioids as the gold standard
framework of a randomized, blinded, controlled trial.
Therefore, our study will expand the literature by pro-
viding information regarding the safety and efficacy of
low-dose ketamine (0.3 mg/kg) in comparison with mor-
phine (0.1 mg/kg) in a randomized, blinded, controlled
trial.
This trial will be the largest to date to address this
question in an adult population.
Strengths and limitations
Strengths of this study include blinding; we aim to blind
participants, healthcare providers, and outcome asses-
sors to treatment allocation. We also use ketamine, an
easily accessible and readily available intervention. A
limitation of this study is that it is a single-center study
Additional files
Additional file 1: SPIRIT checklist. (DOCX 45 kb)
Additional file 2: Ketamine for acute painful crisis in sickle cell disease
patients—recognition pathway. (DOCX 115 kb)
Additional file 3: Ketamine for acute painful crisis in sickle cell
disease—pain algorithm. (DOCX 176 kb)
Funding
The study receives no funding from any governmental or commercial agency.
Clinical research operational and management cost is integrated within the
processes of the clinical research program in our institution. The drug costs
were covered by the hospital as part of supporting research activities in the
department (both drugs are of reasonable cost).
Availability of data and materials
All datasets that will be generated and analyzed in this study will be
included in the published article and its supplementary information files.
Results will be posted to the clinicaltrials.gov site as planned; data sharing
will include posting the results at the official study and department social
media accounts (twitter@ketamineScd).
Authors’ contributions
All listed authors are part of the steering committee and were involved in all
meetings conducted. The Research Unit at the Emergency Medicine
Department is operated by the primary investigator, senior investigators,
research coordinators, research nurses, and a biostatistician. At regular face-
to-face meetings, we managed protocol implementation, patient enrolment,
and data validation. The Steering Committee communicated throughout the
trial, overseeing recruitment and any methodological issues that arose. This
committee will create and review study guidelines and publications related to
Alshahrani et al. Trials (2019) 20:286 Page 7 of 7

the study. We will publish the protocol under group authorship, acknowledging
the responsibilities of all co-investigators. All co-investigators contributed to the
protocol design and review before submission according to their interest and
scientific expertise. 1. Conception and design: MS, MT, LP. 2. Acquisition, analysis
and interpretation: MS, LP, AS, MT, MJ, TJ, MH, MF, NM, SN, OF, HM, MM, SF, MD,
SK, SO, BK, MN, AA, TM, DA, SD, DF, WH. 3. Drafting the manuscript for
important intellectual content: MS, LP, AS, MT, MJ, TJ, MH, MF, NM, SN,
OF, HM, MM, SF, MD, SK, SO, BK, MN, AA, TM, DA, SD, DF, WH. 4. All
authors read and approved the final manuscript.
Ethics approval and consent to participate
This protocol is designed according to the new paragraph 6 of the Declaration
of Helsinki (Edinburgh Update, 2000), which states that even the best proven
interventions must be evaluated continually through research for their safety,
effectiveness, efficiency, accessibility, and quality [22].
Prior to the start of the study, the protocol and the informed consent form
and other applicable documentation was submitted to and approved by our
local Institutional Review Board (IRB 2016–01-042). Documentation of Ethics
Committee/IRB approvals are required before projects are activated to
register and enroll patients. Enrollment began in February 2018.
We anticipate completion of enrollment by the end of January 2019.
Consent for publication
Not applicable. No patients were involved in the trial design or recruitment,
or in any part of the study methods.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published
maps and institutional affiliations.
Author details
1
Emergency and Critical Care Departments, King Fahad Hospital of the
University, Imam Abdulrahman bin Faisal University-Dammam, AlKhobar,
Kingdom of Saudi Arabia. 2Anesthesia Department, King Fahad Hospital of
the University, Imam Abdulrahman bin Faisal University-Dammam, Kingdom
of Saudi Arabia, Mansoura University, Mansoura, Egypt. 3Emergency
Department, King Fahad Hospital of the University, Imam Abdulrahman bin
Faisal University-Dammam, AlKhobar, Kingdom of Saudi Arabia. 4Pharmacy
Department, King Fahad Hospital of the University, AlKhobar, Kingdom of
Saudi Arabia. 5Department of Clinical Epidemiology and Biostatistics,
McMaster University, Hamilton, Canada.
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Received: 12 August 2018 Accepted: 4 May 2019

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